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- PDB-5ei6: Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopola... -

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Basic information

Entry
Database: PDB / ID: 5ei6
TitleRapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach
ComponentsDual specificity protein kinase TTK
KeywordsTRANSFERASE / Spindle Assembly Checkpoint (SAC) / Oncology target Pyrido[3 / 4-d]pyrimidine based inhibitors Selective against MPS1
Function / homology
Function and homology information


protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / protein serine/threonine/tyrosine kinase activity / mitotic spindle organization ...protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / protein serine/threonine/tyrosine kinase activity / mitotic spindle organization / chromosome segregation / spindle / kinetochore / protein tyrosine kinase activity / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of cell population proliferation / ATP binding / membrane / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Protein kinase Mps1 family / Tetratricopeptide-like helical domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Protein kinase Mps1 family / Tetratricopeptide-like helical domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-5OQ / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.01 Å
AuthorsInnocenti, P. / Woodward, H.L. / Solanki, S. / Naud, N. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. ...Innocenti, P. / Woodward, H.L. / Solanki, S. / Naud, N. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. / Faisal, A. / Mak, G. / Box, G. / Valenti, M. / De Haven Brandon, A. / O'Fee, L. / Saville, J. / Schmitt, J. / Burke, R. / van Montfort, R.L.M. / Raymaud, F.I. / Eccles, S.A. / Linardopoulos, S. / Blagg, J. / Hoelder, S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UK United Kingdom
CitationJournal: J.Med.Chem. / Year: 2016
Title: Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.
Authors: Innocenti, P. / Woodward, H.L. / Solanki, S. / Naud, S. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. / Faisal, A. / Mak, G.W. / Box, G. / Valenti, M. / ...Authors: Innocenti, P. / Woodward, H.L. / Solanki, S. / Naud, S. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. / Faisal, A. / Mak, G.W. / Box, G. / Valenti, M. / De Haven Brandon, A. / O'Fee, L. / Saville, H. / Schmitt, J. / Matijssen, B. / Burke, R. / van Montfort, R.L. / Raynaud, F.I. / Eccles, S.A. / Linardopoulos, S. / Blagg, J. / Hoelder, S.
History
DepositionOct 29, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 20, 2016Provider: repository / Type: Initial release
Revision 1.1May 11, 2016Group: Database references
Revision 1.2Aug 30, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dual specificity protein kinase TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6324
Polymers36,1151
Non-polymers5173
Water1,29772
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area460 Å2
ΔGint2 kcal/mol
Surface area12610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.960, 104.044, 111.279
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Dual specificity protein kinase TTK / Phosphotyrosine picked threonine-protein kinase / PYT


Mass: 36115.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-(2,4-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine
Source: (gene. exp.) Homo sapiens (human) / Gene: TTK, MPS1, MPS1L1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-5OQ / ~{N}-(2,4-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)isoquinolin-3-amine


Mass: 360.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20N4O2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 72 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.84 Å3/Da / Density % sol: 56.65 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M BIS-TRIS Propane, 0.2 M MgCl2, 0.2 M Sodium formate, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Mar 13, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.01→40.17 Å / Num. obs: 29341 / % possible obs: 99.7 % / Redundancy: 20 % / Biso Wilson estimate: 39.26 Å2 / Net I/σ(I): 17.1

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.01→38 Å / Cor.coef. Fo:Fc: 0.9573 / Cor.coef. Fo:Fc free: 0.954 / SU R Cruickshank DPI: 0.126 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.126 / SU Rfree Blow DPI: 0.117 / SU Rfree Cruickshank DPI: 0.118
RfactorNum. reflection% reflectionSelection details
Rfree0.2205 1419 4.89 %RANDOM
Rwork0.1967 ---
obs0.1978 28997 99.63 %-
Displacement parametersBiso mean: 52.83 Å2
Baniso -1Baniso -2Baniso -3
1-5.3645 Å20 Å20 Å2
2---6.4457 Å20 Å2
3---1.0812 Å2
Refine analyzeLuzzati coordinate error obs: 0.286 Å
Refinement stepCycle: 1 / Resolution: 2.01→38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2047 0 35 72 2154
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012127HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.032886HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d710SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes330HARMONIC5
X-RAY DIFFRACTIONt_it2127HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.96
X-RAY DIFFRACTIONt_other_torsion17.74
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion288SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2433SEMIHARMONIC4
LS refinement shellResolution: 1.97→2.04 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2085 125 4.44 %
Rwork0.2018 2689 -
all0.2021 2814 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.93591.48620.22591.0166-1.0392.928-0.0701-0.3107-0.31720.14270.0467-0.149-0.1207-0.03310.0234-0.0893-0.01690.0435-0.04140.0641-0.07056.040521.1711-13.6047
23.1751-0.61560.40661.9291-0.71993.04930.0878-0.0752-0.4775-0.1652-0.08750.30240.3264-0.0928-0.0003-0.15990.0051-0.0216-0.06110.0885-0.0301-10.888110.968-27.2886
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|516 - 620}
2X-RAY DIFFRACTION2{A|621 - 794}

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